Breast cancer is one of the most prevalent types of cancer, and epidemiological and clinical studies have shown that approximately one-third of breast tumors are estrogen-dependent. This means that estrogens are required for the growth of such breast tumors in both premenopausal and postmenopausal patients. In postmenopausal women, in whom breast cancer most commonly occurs, breast tumor concentrations of estrone and estradiol are considerably higher than blood estrogen levels. Although retention of estrogens in breast tumors by high-affinity binding proteins contributes to the level of estrogens in tumors, estrogen concentrations in the breast are higher than plasma levels in breast cancer patients regardless of whether their tumors are estrogen receptor-positive (ER+) or receptor-negative (ER-). In situ formation of estrogen from estrogen biosynthetic precursors within tumors is now known to make a major contribution to the estrogen content of breast tumors.
The enzymes required for estradiol biosynthesis (i.e., aromatase, 17.beta.-hydroxy-steroid dehydrogenase, and estrone sulfatase) are present in normal and malignant breast tissues. Blood concentrations of estrone sulfate are 8- to 10-fold greater than those of unconjugated free estrone, and breast tissue concentrations of estrone sulfatase activity, the enzyme responsible for the conversion of estrone sulfate to estrone, are a thousand-fold higher than those of aromatase activity. Together, these findings suggest that estrone sulfatase plays a key role in regulating the formation of estrogens within breast tumors, particularly in postmenopausal women. See, e.g.: Pasqualini et al., Ann. N.Y. Acad. Sci. 464:106-116 (1986); Santner et al., J. Clin. Endocrinol. Metabol. 59(1):29-33 (1984); Evans et al., J. Steroid Biochem. Mol. Biol. 39:493-499 (1991); Pasqualini et al., J. Steroid Biochem. Mol. Biol. 41(308):323-329 (1992); Vignon et al., Endocrinology 106(4):1079-1086 (1980); and Santner et al., Int. J. Cancer 54:119-124 (1993). ##STR2##
There is additional evidence of the relative significance of the aromatase pathway and the estrone sulfatase pathway in providing sufficient estrogen to sustain tumor growth. In postmenopausal women, the levels of estradiol in breast tumor tissues are 10 to 40 times higher than in plasma and are similar to those in premenopausal women, even though plasma estrogen levels are much lower after the menopause. This concentration gradient is not entirely due to estradiol uptake and binding to estrogen receptors, since tissue estradiol levels correlate poorly with estrogen receptor levels.
In situ production of estradiol, through either the aromatase or the estrone sulfatase pathway, could affect this gradient. The level of estrone sulfate present in the serum of postmenopausal women is 10 times higher than the level of free estrogens (Prost et al., Cancer Res. 44:661-664 (1984)). Serum estrone sulfate levels are also higher in postmenopausal women with breast cancer than in normal postmenopausal women (Purohit et al., Int. J. Cancer 50:901-905 (1992)). Also, sulfatase levels in tumors are much higher than aromatase levels (Pasqualini et al., J. Steroid Biochem. 34(1-6):155-163 (1989); Adams et al., Cancer Res. 39:5124-5126 (1979)). The absolute levels of aromatase activity in tumors are relatively low, ranging from 5 to 80 pmol/g protein/h. Bradlow (Bradlow et al., Cancer Res. (Suppl.) 42:3382s-3386s (1982)) and others consider this degree of tumor aromatase activity too low for a biologically meaningful level of estradiol to be synthesized locally within the tumor.
Quantitative information on the local production of estrogen shows that the sulfatase activity in breast tumors is more than 10 times the aromatase activity. When sulfatase and aromatase activity in human tumors were compared at physiological levels of substrate, sulfatase produced 2.8 pmol estrone/g protein/h while aromatase produced only 0.27 pmol/g protein/h. Consequently, estrone sulfate represents one of the most important precursors for tissue production of estradiol, and estrone sulfatase is a quantitatively more important local route for estrogen production than aromatase.
To date, little work has been done in the development of estrone sulfatase inhibitors. Li et al., Steroids 60 (March 1995), at pages 299-306, evaluate several compounds as potential inhibitors of human placental sterylsulfatase, but do not identify any highly potent estrone sulfatase inhibitors. Similarly, Duncan et al., Cancer Research 53:298-303 (1993), evaluate a potential estrone sulfatase inhibitor, estrone-3-methylthiophosphonate, but conclude that the experimental work done with that compound would hopefully lead to development of "more efficient" inhibitors of the enzyme.
Accordingly, the present invention is directed to novel compounds that are extremely effective estrone sulfatase inhibitors. The invention thus represents a significant advance in the art, particularly in the treatment of breast cancer and other diseases and conditions that are potentiated by the presence of estrogens.
In addition to the aforementioned references, the following pertain to one or more aspects of the invention and as much may be of background interest to those skilled in the art: Howarth et al., J. Med. Chem. 37:219-221 (1994) and PCT Publication No. WO93/05064 relate to estrone sulfamates as inhibitors of steroid sulfatases, with Howarth et al. specifically focused on inhibition of estrone sulfatase; and U.S. Pat. Nos. 3,033,860 to Kuehne and 4,297,350 to Babcock et al., which describe steroids having an additional cyclic structure adjacent to the "A" ring.
No art of which applicants are aware, however, describe compounds as provided herein, to inhibit estrone sulfatase or for any other purpose. To the best of applicants' knowledge, then, the compounds and methods of the invention are previously unknown and completely unsuggested by the art.